Endocrinology

Super-conserved Receptors Expressed in Brain (SREB) are a family of orphan G protein coupled receptors with three members in most vertebrates (GPR27 or SREB1, GPR85 or SREB2, and GPR173 or SREB3). They are associated with diverse physiological processes, ranging from glucose homeostasis to ovarian development. Despite a lack of confirmed ligands, our understanding of these receptors has increased…

Acromegaly is a rare disease caused by growth hormone (GH) hypersecretion from a pituitary adenoma. Pegvisomant is the only approved GH receptor antagonist (GHRA) and is administered via daily subcutaneous injections, which limits real-world effectiveness. Here, we report the discovery and characterization of MAR002, a novel, half-life extended monoclonal antibody GHRA. MAR002 was identified by i…

Socio-sexual behaviors, a key aspect of mammalian biology, are governed by evolutionarily conserved neuronal circuits that control partner preference, sexual attraction, and attachment. This mini-review summarizes recent advances in understanding neuroendocrine pathways involved in various levels of socio-sexual interactions, from mating preferences to forming long-term sexual partnerships. We fi…

Cancers of the breast and prostate are one of the leading causes of cancer deaths in women and men, respectively. Although several treatment options have been developed to transform these cancers into manageable chronic diseases, they still contribute to over 70,000 deaths each year in the United States. Though majority of these cancers belong to slow growing differentiated subtypes, the cancers …

Serotonin neurons are thought to exert a modulatory influence on the secretion of the gonadotropin hormones in mammals, but their mechanism of action remains unclear. We examined here the potential role of serotonin neurons in modulating the activity of the gonadotropin-releasing hormone (GnRH) pulse generator formed by the arcuate nucleus kisspeptin (ARNKISS) neurons. Acute brain slice electroph…

Growth hormone (GH) controls sexual dimorphism in hepatocyte gene expression programs governing lipid metabolism, bile acid synthesis and xenobiotic processing, which contribute to sex differences in metabolic dysfunction-associated steatotic liver disease (MASLD) risk. Although GH-regulated sex-specific transcription is well-studied, the functional cis-regulatory hepatocyte enhancers that orches…

The clinical characteristics of type 2 diabetes (T2D) differ between the sexes. For example, the risk of T2D is higher in males than in premenopausal females, whereas the risk of T2D-associated cardiovascular disease is higher in females. However, the sex-dependent mechanisms of T2D pathogenesis remain incompletely understood. Publicly available human islet datasets, such as HPAP and Humanislets.…

Orthopedia (Otp) transcription factor is a critical determinant in the development of the neuroendocrine hypothalamus, and its embryonic deletion results in lethality. Although Otp expression is maintained throughout life, its physiological function in adulthood is not well understood. Here, we generated a forebrain-specific, tamoxifen-inducible, conditional knockout mouse model to investigate th…

A large "gene desert" located far upstream from Fshb and Kcna4 contains several gonadotrope-specific accessible chromatin sites which were seen in chromatin conformation capture (3C) to make distinct contacts with both genes. Expression of Fshb and Kcna4 was strongly inhibited by JQ-1, which represses super-enhancer activity, and the region displays super-enhancer characteristics. The sites of op…

Effector kinases of the lipid second messenger diacylglycerol (DAG), including protein kinase C (PKC) and protein kinase D (PKD) isozymes, have been widely implicated in the development and progression of prostate cancer. By acting as central hubs of growth factor-mediated signaling, these kinases integrate oncogenic signals with the androgen receptor (AR) pathway, contributing to prostate tumor …

Estradiol's binding to HSA is a dynamic, multi-equilibrium process driven by ligand-induced conformational rearrangements within HSA; the binding data are inconsistent with canonical model of estradiol-HSA interaction with 1:1 stoichiometry and a fixed Kd.

Polycystic ovary syndrome (PCOS) is a systemic endocrine disorder characterized by perturbations in both androgen and insulin signaling pathways that result in anovulatory infertility and metabolic syndrome. This study aimed to elucidate insulin signaling in the PCOS ovary using a mouse model that develops both the metabolic and reproductive manifestations of PCOS due to chronic postnatal dihydro…

Missense mutations in nuclear receptors (NR) transcription factors (TF) cause a number of genetic disorders, including PPARG mutations that result in familial partial lipodystrophy type 3 (FPLD3). Experimental assessment is essential to establish a newly identified mutation as disease-causing, as accurately predicting the effect of new mutation in silico remains challenging due to the multifuncti…

The circadian clock plays a critical role in coordinating energy metabolism across tissues, including brown adipose tissue (BAT), a major site of nonshivering thermogenesis. This study aimed to elucidate the cell-autonomous role of the peripheral circadian clock in brown adipocyte thermogenesis using an in vitro model independent of extrinsic cues. Primary brown adipocytes were differentiated fro…

The binding of human growth hormone (hGH) to the human growth hormone receptor (hGHR) is a key endocrinological process that controls critical aspects of cell growth, proliferation, and differentiation. Mechanistically, this sequential, asymmetric binding event involves the interaction between a single hGH molecule and distinct sites (sites 1 and 2) on the extracellular domain of a preformed hGHR…

High ovarian cancer cell glucocorticoid receptor (GR) expression is associated with reduced progression-free survival (PFS) despite standard debulking surgery and adjuvant chemotherapy. Although not previously linked to tumor-cell GR expression, a "cold" (immune-suppressive) ovarian cancer tumor microenvironment (TME) is also associated with poor prognosis. In this study, analysis of The Cancer G…

Androgen biosynthesis is physiologically necessary for generating the principal stimulus for androgen receptor (AR) signaling and thus plays an essential role for development of the normal prostate, prostate cancer growth, and the development of resistance to hormonal therapies. Testosterone and dihydrotestosterone are both potent endogenous androgens that stimulate AR signaling. While the role o…

Activin-class ligands of the transforming growth factor β family induce follicle-stimulating hormone (FSH) production by pituitary gonadotrope cells in mice via the actions of the transcription factors SMAD3, SMAD4, and FOXL2, which bind to cis-elements in the FSHβ subunit (Fshb) promoter. An enhancer region for murine Fshb transcription was identified in vitro. However, deletion of the region us…

Anti-Müllerian hormone (AMH) is produced by granulosa cells within growing ovarian follicles and limits the number of follicles reaching ovulation. AMH is synthesized as a precursor protein comprising N-terminal prodomains and C-terminal mature domains, separated by a furin-like cleavage motif (RXXR). Proteolytic maturation of AMH (140 kDa) is required to release the bioactive mature dimer (25 kD…